This invention relates to an improved, cost effective and industrially advantageous process for the preparation of (3R,4S)-1-(4-Fluorophenyl)-3-[3(S)-3-(4-fluorophenyl)-3-hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone (Ezetimibe), useful as cholesterol absorption inhibitor, claimed in U.S. Pat. No. 5,767,115. Preparation of Ezetimibe is also described in the above said patent. It comprises of (S)-4-phenyl-2-oxazolidinone is reacted with methyl-4-(chloroformyl)butyrate to obtain a compound of ester and it is condensed with 4-benzyloxy benzylidine (4-fluoro) aniline in the presence of titanium isopropoxide and titanium tetrachloride to give an amide compound and it is cyclised in the presence of tetrabutyl ammonium fluoride and bis trimethyl silyl acetamide to give protected lactam, it undergoes hydrolysis to give a carboxylic acid and further it reacts with p-fluoro phenyl magnesium bromide and zinc chloride in the presence of tetrakis (triphenyl phosphine) palladium to give an aromatic ketone, it is further reduced selectively in the presence of chiral catalyst to obtain an hydroxy compound and it undergoes debenzylation to give the title compound of formula-I.
By following the above process in the hydrolysis stage after completion of the reaction, pH adjusted to acidic side (below pH-4) and extracting the compound resulted more impure product because as the Lactam ring is acid sensitive, it is opened up while adjusting the pH to below 4. In the organometallic condensation reaction between acid chloride and para fluoro phenyl zinc halide, tetrakis (triphenyl phosphine) palladium is used as a catalyst which is highly expensive as well as molecular weight is higher which resulted in more byproducts and obtained compound is less pure.
The above said process is both uneconomical, inconsistency in reproducibility and more of byproduct/waste generation like triphenyl phosphine oxide, DMS, etc., and hence it is not suitable for commercial production.
Therefore, the main objective of the present invention is to prepare formula-1 through a process which is cost-effective, commercially viable, eco-friendly and consistent.
The formula-1 is prepared in the present invention, in a novel process that is cost effective and suitable for commercial scale up.